HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 46, 33412-33420, November 16, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/46/33412    most recent M706799200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jacobs, A. T. Articles by Marnett, L. J. Search for Related Content PubMed PubMed Citation Articles by Jacobs, A. T. Articles by Marnett, L. J. Social Bookmarking                      What's this?

Heat Shock Factor 1 Attenuates 4-Hydroxynonenal-mediated Apoptosis

CRITICAL ROLE FOR HEAT SHOCK PROTEIN 70 INDUCTION AND STABILIZATION OF Bcl-X_L^*

From the Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146

Lipid peroxidation is a consequence of both normal physiology and oxidative stress that generates various reactive metabolites, a principal end product being 4-hydroxynonenal (HNE). As a diffusible electrophile, HNE reacts extensively with cellular nucleophiles. Consequently, HNE alters cellular signaling and activates the intrinsic apoptotic cascade. We have previously demonstrated that in addition to promoting apoptosis, HNE activates stress response pathways, including the antioxidant, endoplasmic reticulum stress, DNA damage, and heat shock responses. Here we demonstrate that activation of the heat shock response by HNE is dependent on the expression and nuclear translocation of heat shock factor 1 (HSF1), which promotes the expression of heat shock protein 40 (Hsp40) and Hsp70-1. Ectopic expression and immunoprecipitation of c-Myc-tagged Hsp70-1 indicates that HNE disrupts the inhibitory interaction between Hsp70-1 and HSF1, leading to the activation heat shock gene expression. Using siRNA to silence HSF1 expression, we observe that HSF1 is necessary for the induction of Hsp40 and Hsp70-1 by HNE, and the lack of Hsp expression is correlated with an increase in apoptosis. Nrf2, the transcription factor that mediates the antioxidant response, was also silenced using siRNA. Silencing Nrf2 also enhanced the cytotoxicity of HNE, but not as effectively as HSF1. Silencing HSF1 expression facilitates the activation of JNK pro-apoptotic signaling and selectively decreases expression of the anti-apoptotic Bcl-2 family member Bcl-X_L. Overexpression of Bcl-X_L attenuates HNE-mediated apoptosis in HSF1-silenced cells. Overall, activation of HSF1 and stabilization of Bcl-X_L mediate a protective response that may contribute significantly to the cellular biology of lipid peroxidation.

Received for publication, August 15, 2007

^* This work was supported by NIEHS, National Institutes of Health Program Project Grant P01ES013125. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-0146. Tel.: 615-343-7329; Fax: 615-343-7534; E-mail: larry.marnett{at}vanderbilt.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				A. T. Jacobs and L. J. Marnett HSF1-mediated BAG3 Expression Attenuates Apoptosis in 4-Hydroxynonenal-treated Colon Cancer Cells via Stabilization of Anti-apoptotic Bcl-2 Proteins J. Biol. Chem., April 3, 2009; 284(14): 9176 - 9183. [Abstract] [Full Text] [PDF]